REPORTS

Cite as: J. S. Lavine et al., Science

10.1126/science.abe6522 (2021).

Immunological characteristics govern the transition of

COVID-19 to endemicity
Jennie S. Lavine1*, Ottar N. Bjornstad2, Rustom Antia1
1
Department of Biology, Emory University, Atlanta, GA 30322, USA. 2Department of Biology and Center for Infectious Disease Dynamics, The Pennsylvania State University,
University Park, PA 16802, USA.
*Corresponding author. Email: jslavin@emory.edu

We are currently faced with the question of how the CoV-2 severity may change in the years ahead. Our
analysis of immunological and epidemiological data on endemic human coronaviruses (HCoVs) shows that
infection-blocking immunity wanes rapidly, but disease-reducing immunity is long-lived. Our model,
incorporating these components of immunity, recapitulates both the current severity of CoV-2 and the

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benign nature of HCoVs, suggesting that once the endemic phase is reached and primary exposure is in
childhood, CoV-2 may be no more virulent than the common cold. We predict a different outcome for an
emergent coronavirus that causes severe disease in children. These results reinforce the importance of
behavioral containment during pandemic vaccine rollout, while prompting us to evaluate scenarios for
continuing vaccination in the endemic phase.

Humans have regularly been threatened by emerging patho-
gens that kill a substantial fraction of all people born. Recent
decades have seen multiple challenges from acute virus infec-
tions including SARS, MERS, Hendra, Nipah and Ebola. For-
tunately, all were locally contained. When containment is not
immediately successful, as is likely for the novel betacorona-
virus SARS CoV-2 (CoV-2) (1, 2), we need to understand and
plan for the transition to endemicity and continued circula-
tion, with possible changes in disease severity due to virus
evolution and build-up of host immunity and resistance.
CoV-2 is an emerging virus that causes COVID. The virus
has a high basic reproductive number (R0) and which is trans-
missible during the asymptomatic phase of infection, both of
which make it hard to control (3). However, there are six
other coronaviruses with known human chains of transmis-
sion, which may provide clues to future scenarios for the cur-
rent pandemic. There are four human coronaviruses (HCoVs)
that circulate endemically around the globe; they cause only
mild symptoms and are not a significant public health bur-
den (4). Another two HCoV strains, SARS CoV-1 and MERS,
emerged in recent decades and have higher case fatality ra-
tios (CFRs) and infection fatality ratios (IFRs) than COVID-
19 but were contained and never spread widely (5, 6).
We propose a model to explore the potential changes in
both transmission and disease severity of emerging HCoVs
through the transition to endemicity. We focus on CoV-2 and
discuss how the conclusions would differ for emerging coro-
naviruses more akin to SARS and MERS. Our hypothesis is
that all HCoVs elicit immunity with similar characteristics,
and the current acute public health problem is a consequence
of epidemic emergence into an immunologically naïve
population in which older age-groups with no previous expo-
sure are most vulnerable to severe disease. We use our esti-
mates of immunological and epidemiological parameters for
endemic HCoVs to develop a quantitative model for endemic
transmission of a virus with SARS-CoV-2 -like characteristics,
including the age-dependence of severity. Our model explic-
itly considers three separate measures for immune efficacy
that wane at different rates (fig. S1).
Building on ideas from the vaccine modeling literature,
immunity may provide protection in three ways (7). In its
most robust form, “sterilizing” immunity can prevent a path-
ogen from replicating, thereby rendering the host refractory
to reinfection. We term this property immune efficacy with
respect to susceptibility, IES. If immunity does not prevent
reinfection, it may still attenuate the pathology due to rein-
fection (IEP) and/or reduce transmissibility or infectiousness
(IEI). Indeed, experimental reexposure studies on endemic
HCoVs provide evidence that the three IE’s do not wane at
the same rate (8, 9). Callow’s experimental study (8) shows
that reinfection is possible within one year (relatively short
IES); however, upon reinfection symptoms are mild (high IEP)
and the virus is cleared more quickly (moderate IEI). Details
on the derivation of the model can be found in section 2 of
the supplementary materials (SM).
We reanalyze a detailed dataset that estimates age-spe-
cific seroprevalence based on both IgM (acute response) and
IgG (long-term memory) against all four circulating HCoVs
in children and adults (10) to estimate parameter ranges for
transmission and waning of immunity (see Fig. 1A). The rapid
rise in both IgM and IgG seroprevalence indicates that pri-
mary infection with all four endemic HCoV strains happens

First release: 12 January 2021 www.sciencemag.org (Page numbers not final at time of first release) 1
early in life, and our analysis of these data gives us an esti-
mate for the mean age of primary infection (MAPI) between
3.4 and 5.1 years, with almost everyone infected by age 15 (see
SM section 1 for details). The absence of detectable IgM titers
in any individual over the age of 15 years suggests reinfec-
tions of adults causes a recall response, indicating that while
CoV specific immunity may wane it is not lost. Whether im-
munity would wane to naïve levels in the absence of high
pathogen circulation remains an open question.
For most people to be infected so early in life—younger
even than measles in the pre-vaccine era—the attack rate
must exceed transmission from primary infections alone. The
model shows a high attack rate can arise from a combination
of high transmissibility from primary infections (i.e., high R0),
waning of sterilizing immunity and significant transmission
from reinfections in older individuals. The rapid waning of
sterilizing immunity is also reported in experimental HCoV
infections of humans which showed that reinfection is possi-
ble 1 year after an earlier infection, albeit with milder symp-
toms (IEP) and a shorter duration (IEI) (11). Figure 1B shows
the plausible combinations of waning immunity and trans-
mission from reinfected individuals that are required to pro-
duce the MAPI observed in Fig. 1A, based on steady-state
infection levels (see SM section 2.1 for details). Table 1 shows
the ranges of the parameters used in our simulations.
At the beginning of an outbreak, the age distribution of
cases mirrors that of the population (Fig. 2A). However, once
the demographics of infection reaches a steady state, our
model predicts primary cases occur almost entirely in babies
and young children, who in the case of COVID-19, experience
a low CFR and a concomitantly low infection fatality ratio
(IFR). Reinfections in older individuals are predicted to be
common during the endemic phase and contribute to trans-
mission, but in this steady-state population, older individu-
als, who would be at risk for severe disease from a primary
infection, have acquired disease-reducing immunity follow-
ing infection during childhood. The top panel of Fig. 3B illus-
trates how the overall IFR for CoV-2 drops dramatically,
eventually falling below that of seasonal influenza (approxi-
mately 0.001) once the endemic steady-state is reached.
The time it takes to complete the shift in IFR as endemic-
ity develops depends on both transmission (R0) and loss of
immunity (ω and ρ), as is shown in Fig. 2B and fig. S4. The
transition from epidemic to endemic dynamics is associated
with a shift in the age-distribution of primary infections to
lower age groups (Fig. 2A). This transition may take any-
where from a few years to a few decades depending on how
fast the pathogen spreads. The rate of spread, measured by
R0, is determined by a combination of viral properties and the
frequency of social contacts, and may therefore be reduced by
social distancing. The top panel shows the effect of reducing
R0 to 2, whereas the middle and bottom panels show the
First release: 12 January 2021 www.sciencemag.org
dynamics for higher R0, which are more akin to those of CoV-
2 in the absence of control measures. If transmission is high,
the model predicts a high case load and death rate in earlier
years following emergence (Fig. 2 and fig. S5). In Fig. 2B we
see that, as might be expected, longer lasting sterilizing im-
munity slows down the transition to endemicity.
These results are robust to a more biologically realistic
distribution for the duration of sterilizing immunity and the
possibility that the generation of protective immunity re-
quires more than one infection (see SM section 3 and figs. S5
to S9).
Slowing down the epidemic through social distancing
measures that reduce R0 to close to one flattens the curve,
thus delaying infections and preventing most deaths from
happening early on, affording critical time for the develop-
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ment of an effective vaccine (fig. S10). If vaccine-induced IES
and IEP immunity is similar to that induced by HCoV infec-
tions, the vaccine may usher in the endemic regime more
quickly. The model code (see acknowledgments) provides a
flexible scaffolding for studying alternative vaccination sce-
narios. Notably, the model predicts that once the endemic
state is reached, mass vaccination may no longer be necessary
to save lives (see SM section 4 and fig. S11).
We can extend our predictions to two other potentially
emerging coronavirus infections—SARS and MERS. Our
model predicts that in the endemic state the IFR of a circu-
lating CoV depends primarily on the severity of childhood in-
fections. In the case of CoV-1, which is more pathogenic than
CoV-2, we still expect a low disease burden in the endemic
phase because CoV-1, like CoV-2, has a low IFR in the young
(Fig. 3). However, data suggest not all emerging HCoVs follow
this optimistic pattern; the overall IFR of an endemic MERS-
like virus would not decrease during the transition to ende-
micity as seen in Fig. 3B, and this is because disease severity
(and IFR) is high in children, the age group expected to expe-
rience the bulk of primary cases during the endemic phase.
In the endemic phase, a vaccination program against MERS
would therefore be necessary to avoid excess mortality (fig.
S11).
The key result from our new model framework that ex-
plicitly recognizes that functional immunity to reinfection,
disease and shedding are different is that, in contrast with
infections that are severe in childhood, CoV-2 could join the
ranks of mild, cold-causing endemic human coronaviruses in
the long run. A critical prediction is that the severity of emer-
gent CoVs once they reach endemicity depends only on the
severity of infection in children (Fig. 3) because all available
evidence suggests immunity to HCoVs has short IES and mod-
erate IEI, leading to frequent reinfection throughout adult-
hood (11, 12) but strong IEP such that childhood infection
provides protection from pathology upon reinfection in
adulthood, as evidenced by the rarity of severe infections or
(Page numbers not final at time of first release) 2
detectable IgM titers in adults. Strain-specific virulence fac-
tors, such as the shared cellular receptor, ACE-2, to which
CoV-1, CoV-2 and the endemic strain NL63 all bind (13–16),
may affect the CFR during the emergence phase but have lit-
tle impact on the severity of disease in the endemic phase.
Because the four endemic HCoVs have been globally circulat-
ing for a long time and almost everyone is infected at a young
age, we cannot ascertain how much pathology would result
from a primary or even secondary case of any of these in an
elderly or otherwise vulnerable person.
The key insights come from how our model explicitly in-
corporates different components of immunological protec-
tion with respect to susceptibility, pathology and infectivity
(IES, IEP and IEI) and their different rates of waning. In our
analysis we hypothesized that these components of immunity
for CoV-2 are comparable to those of endemic HCoVs, and
this needs to be determined. Additionally, during the transi-
tion to endemicity, we need to consider how the IE’s depend
on primary and secondary infections across ages (17) and how
responses differ between vaccination and natural infection.
Longitudinal analysis of CoV-1 patients provides an op-
portunity to measure the durability of immune memory in
the absence of reexposure. The only long-term study we know
of that follows CoV-1-specific antibodies suggests they wane
faster compared with antibodies to other live viruses and vac-
cines such as measles, mumps, rubella and smallpox (18) and
fall below the threshold of detection in six years (19). In con-
trast to antibody responses, memory T cells persist for much
longer periods (19, 20) and confer protection in animal model
systems (21).
We further consider the effects of strain variation both for
natural infection and vaccination. Strain variation and anti-
body escape may occur in endemic strains (22), however the
fact that symptoms are mild suggests that immunity induced
by previously seen strains is nonetheless strong enough to
prevent severe disease. Indeed among HCoVs, frequent rein-
fections appear to boost immunity against related strains
(12). However, the effect of strain variation may differ for vac-
cine-induced immunity, especially in light of the narrower
epitope repertoire of many currently authorized vaccines.
If frequent boosting of immunity by ongoing virus circu-
lation is required to maintain protection from pathology,
then it may be best for the vaccine to mimic natural immun-
ity insofar as preventing pathology without blocking ongoing
virus circulation. Preliminary results suggest the adenovirus-
based vaccine is better at preventing severe than mild or
asymptomatic infections (23), and it will be important to col-
lect similar data for the other vaccines. Should the vaccine
cause a major reduction in transmission, it might be im-
portant to consider strategies that target delivery to older in-
dividuals for whom infection can cause higher morbidity and
mortality, while allowing natural immunity and transmission
First release: 12 January 2021 www.sciencemag.org
to be maintained in younger individuals. During the transi-
tion to endemicity, primary CoV-2 infections will frequently
occur in older individuals, and we need to determine if im-
munity induced by infection or vaccination in adulthood is
similar to that produced by natural infections in childhood.
Thus far, there have been few reinfections reported with CoV-
2, and disease severity has varied (24); the only population-
level study of reinfection of which we are aware estimates a
low rate of reinfection within the first six months after pri-
mary infection and mild disease upon reinfection (25), but
further analysis and monitoring are vital.
The findings presented here suggest that using symptoms
as a surveillance tool to curb the virus’s spread will become
more difficult, as milder reinfections increasingly contribute
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to chains of transmission and population level attack rates.
In addition, infection or vaccination may protect against dis-
ease but not provide the type of transmission-blocking im-
munity that allows for shielding (26) or the generation of
long-term herd immunity (2).
The details of the change in overall IFR through the tran-
sient period will be impacted by a wide array of factors, such
as age-specific human contact rates (27) and susceptibility to
infection (28), as well as improvement in treatment protocols,
hospital capacity, and virus evolution. The qualitative result
of mild disease in the endemic phase is robust to these com-
plexities, but quantitative predictions for the transient phase
will depend on a careful consideration of these realities and
how they interact with the dynamics of infection and compo-
nents of immunity (29).
The changes in the IFR over time predicted by the model
have implications for vaccination strategy against current
and future emerging HCoVs. Social distancing and an effec-
tive vaccine are critical for control during a virgin epidemic
and the transition out of it, but once we enter the endemic
phase, mass vaccination may no longer be necessary. The ne-
cessity for continual vaccination will depend on the age-de-
pendence of the IFR. If primary infections of children are
mild (CoV-1 and CoV-2), continued vaccination may not be
needed as primary cases recede to mild childhood sniffles. If,
on the other hand, primary infection is severe in children (as
for MERS), then vaccination of children will need to be con-
tinued.
From an ecological and evolutionary perspective, our
study opens the door to questions regarding the within-host
and between-host dynamics of human immunity and patho-
gen populations in the face of IE’s with different kinetics. It
also opens the question of how these IE’s interplay with
strain cross-immunity, which is likely relevant within the al-
pha- and beta-coronaviruses. Considering data and model
predictions from emergence through endemicity of HCoVs
revealed a framework for understanding immunity and vac-
cination that may apply to a variety of infections, such as RSV
(Page numbers not final at time of first release) 3
and seasonal influenza, which share similar age distributions
and immune responses.
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ACKNOWLEDGMENTS
We gratefully acknowledge helpful conversations with H. Ahmed, V. Zarnitsyna and
K. Fuller. Funding: This work was funded by NIH grants U01 AI150747, U01
HL139483 and U01 AI144616. Author contributions: J.S.L.: Conceptualization,
Methodology, Software, Formal analysis, Data curation, Writing – original draft,
review and editing, Visualization; R.A.: Conceptualization, Methodology, Writing,
Visualization, Supervision, Funding acquisition; O.N.B.: Conceptualization,
Methodology, Writing – review and editing. Competing interests: The authors
declare no competing interests. Data and materials availability: The scripts and
data used to perform the analysis and generate the figures in this paper are
available on GitHub (https://github.com/JennieLavine/covid-immunity-
endemicity) and archived in Zenodo (35). This work is licensed under a Creative
Commons Attribution 4.0 International (CC BY 4.0) license, which permits
unrestricted use, distribution, and reproduction in any medium, provided the
original work is properly cited. To view a copy of this license, visit
https://creativecommons.org/licenses/by/4.0/. This license does not apply to
figures/photos/artwork or other content included in the article that is credited
to a third party; obtain authorization from the rights holder before using such
material.

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Table 1. Characteristics of coronavirus-immune interactions and relevant parameter ranges.
Characteristic and symbol Estimates from Value Citations
literature (range)
Primary infectious period ≥5.6 days 9 days (8)
(1/γ) ∼10 days (30)

Primary transmissibility 4 to 9 2 to 10 (31)

[R0 = β/(γ + μ)]

Secondary transmissibility 0.35 0 to 1 (8)

(relative to primary, ρ) 0.04 to 0.97 Fig. 2 and fig. S2

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Duration of sterilizing 0.91 years 0.5 to 10 years (8) and SM section 5
immunity (1/ω) 1.67 years (8) and SM section 5
0.5 to 2 years (11, 32)

Relative pathology of mild – (8)

reinfections

Age-specific IFR SARS See (33)

(primary infections) MERS Fig. 3 (5)
COVID-19 (34)

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Fig. 1. A low mean age of primary infection suggests partially transmissible reinfections are common.
(A) Mean proportion seropositive for IgG (green, top lines) and IgM (purple, bottom lines) against the four
endemic HCoV strains [dots connected by dashed lines; vertical lines represent the 95% CI; data from
Zhou et al. (10)]. The mean age of primary infection (MAPI) based on IgM data with 95% CI is shown in text
inside each panel (see SM for details). (B) MAPI as a function of waning of sterilizing immunity (ω, y axis)
and transmissibility of reinfections (ρ, x axis). The MAPI was calculated from the equilibrium dynamics of
the model shown in fig. S1 and supplementary equations 3 to 9 with a plausible basic reproductive number
(R0 = 5) and 0 < ω < 2 and 0 < ρ < 1. See SM section 2.1 for details. The white band in indicates the plausible
combinations of values of ρ and ω consistent with the MAPI for HCoVs estimated in (A). [See fig. S1 for
parallel figures calculated at extreme plausible values for R0 (i.e., R0 = 2 and R0 = 10).]

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Fig. 2. The time scale of the transition from epidemic to endemic dynamics for emerging coronaviruses
depends on R0 and the rate of immune waning. Transition from epidemic to endemic dynamics for emerging
HCoVs, simulated from an extension of the model presented in fig. S1 that includes age structure. Demographic
characteristics (age distribution, birth, and age-specific death rates) are taken from the United States, and
seasonality is incorporated via a sinusoidal forcing function (see SM section 2.2). Weak social distancing is
approximated by R0 = 2. (See figs. S9 to S11 for strong social distancing results, R0 < 1.5.) (A) Daily number of
new infections (black line, calculations in SM section 2.3). An initial peak is followed by a low-incidence endemic
state (years 5 to 10 shown in the inset). A higher R0 results in a larger and faster initial epidemic and more rapid
transition to endemic dynamics. The proportion of primary cases in different age groups changes over time
(plotted in different colors), and the transition from epidemic to endemic dynamics results in primary cases
being restricted to younger age groups. Parameters for simulations: ω = 1 and ρ = 0.7. (B) Time for the average
IFR (6-month moving average) to fall to 0.001, the IFR associated with seasonal influenza. Gray areas represent
simulations where the IFR did not reach 0.001 within 30 years. The time to IFR = 0.001 decreases as the
transmissibility (R0) increases and the duration of sterilizing immunity becomes shorter. Results are shown for
ρ = 0.7. See SM section 2.3 and figs. S4 to S7 for sensitivity analyses and model specifications.

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Fig. 3. The overall infection fatality ratio (IFR) of emerging coronaviruses once they reach endemicity is
strongly influenced by the IFR of young children in the initial epidemic. The age dependence of the IFR
determines how the overall IFR changes during the transition from epidemic to endemic dynamics for emerging
CoVs. (A) Age dependence of the IFRs for the three emerging CoVs. Primary infections with MERS and CoV-1
are consistently symptomatic and the IFR and CFR are therefore assumed to be the same. CoV-1 and CoV-2
have J shaped profiles, with a monotonic increase in IFR with age. The age-specific IFR for MERS is U shaped,
with high mortality in the young and old age groups. Details of the statistical smoothing are described in SM
section 6. (B) The overall IFR changes during the transition to endemic dynamics. These calculations assume
deaths due to reinfections are negligible. We relax this assumption to allow for a slower build-up of immunity
and possible death due to secondary infection in figs. S5 to S9 and show the qualitative results do not change.

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Immunological characteristics govern the transition of COVID-19 to endemicity
Jennie S. Lavine, Ottar N. Bjornstad and Rustom Antia

published online January 12, 2021

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